Creatine (Cr) is an endogenous nutrient that occurs in various tissues of mammalians, for example, in liver, kidneys, muscular tissue, brain tissue, blood, etc.; it appears in a free state, and in the form of Creatine phosphate as well. Creatine is considered a remedy enhancing the energy tissue metabolism that is increasing the energy reserve of ATP, first of all, in the muscular and nerve cells.
In a cell's mitochondria, Creatine interacts reversibly with adenosine triphosphate (ATP), which is caused by the action of the Creatine kinase enzyme with a formation of Creatine phosphate and adenosine diphosphate (ADP). This interaction maintains of the ATP concentration at a constant level at the moments of its intense consumption. There exist other ways for replenishing ATF, such as glycolysis or oxidative phosphorylation, but they refill ATP noticeably slower. Upon consumption of ATP in a cell, a great amount of ADP is released that leads to a transfer of ortho-phosphate from Creatine phosphate to ADP, and the initial ratio between ATP and ADP remains. Due to the high affinity of Creatine kinase to ADP, this process proceeds until a Creatine phosphate concentration falls below several tens μM.
Creatine phosphate (CrP) represents a reserve of macroergic phosphate in maintaining the membrane potential, activation of metabolites or contractive activity of a cell. It maintains the ATP level along with an increasing of energy consumption in a cell, i.e. restores an ortho-phosphate residue on ADP. Like glycogen, CrP is one of the basic sources of the high-energy phosphates transformation cycle, and thereby participates in oxidative phosphorylation of glucose that provides liberation of energy necessary for the functionality of muscular tissue cells, including skeletal muscles and the cardiac muscle. Since Creatine phosphate provides for regenerating ATP with a significant speed, which is achieved by glycogen, an increase of Creatine amount in the muscles raises the muscles capacity of CrP, enhances the muscles workability and increases the muscle bulk.
Creatine phosphate and Creatine are also allosteric regulators of cell processes. It was shown that per os administration of Creatine increases the total Creatine content in an organism. So, administration of Creatine monohydrate at dosages up to 30 g for a few days causes an increase of the total Creatine content in a human's skeleton muscles by more than 20%. These properties attract a special attention due to the possibility of usage of Creatine monohydrate as a food additive for organism enforcement and increase of workability especially in its usage as an addition to the sportsman diet. So, administering Creatine monohydrate in a daily dose 15 g for at least 2 days is used for increasing the muscle force (WO 94/02127, 1994). Nowadays Creatine is recommended as a food additive that is especially important for aged people and vegetarians as there is an expressed tendency to decreasing the Creatine level in the muscles at these groups. The additives are used as a dry powder, liquid or in a semi-liquid form (WO 97/45026, 1997). The composition prepared on their basis are stable in the refrigerator at a temperature of (+)4° C. for a long time, but it degrades at the room temperature during one week.
Besides the use in the food industry, Creatine and Creatine phosphate have wide applications in medicine. For example, Creatine, Creatine phosphate, and cyclo-Creatine (U.S. Pat. No. 6,706,764, 2004) are recommended for the treatment of nervous system diseases such as diabetic and toxic neuropathies, Alzheimer's disease, Parkinson's disease, stroke etc., and also disturbances of metabolism as hyperglycemia and diabetes mellitus (U.S. Pat. No. 6,193,973, 2001). Per os administration of Creatine is described to be used for the treatment of cardiac insufficiency and respiratory failure (WO/EP97/06225, 1999), and also of asthma (U.S. Pat. No. 6,093,746, 2000). The use of Creatine phosphate is shown for the treatment of cardiovascular diseases, promising for the treatment of new-growth tissue (U.S. Pat. No. 5,219,846, 1993).
At the same time the use of Creatine and Creatine phosphate is limited because of poor solubility and instability in aqueous media at physiological pH-values (RU 2295261, 2007). Moreover, Creatine is poorly absorbed from the gastrointestinal tract; the absorption degree is 1÷14%. This requires high usage doses of Creatine. For the effective use of Creatine, compositions produced at the present time require consumption in an amount up to 20 g per day. At the same time, besides increasing the therapy cost, administering high doses of Creatine may lead to negative consequences for the organism, such as disturbance of nitrogen exchange, gastrointestinal disorders, diarrhea, etc.
Therefore preparation of Creatine derivatives possessing a greater stability or higher biological activity represents a big interest that allows, on the one hand, reducing the dose of administered substance and, on the other hand, finding new fields of application therefor.
Derivatives of Creatine and different organic acids have attracted the greatest interest. There is known the use of Creatine pyruvates (U.S. Pat. No. 6,166,249, 2000; RU 2 114 823, 1998) for increasing the workability, for reduction of the body weight, for adaptation to oxygen deficiency conditions at ischemia, the use as a food additive, for skin protection against ageing and sun affection (U.S. Pat. No. 7,186,754, 2007), in the treatment of female sexual disorders, in particular, dysmenorrhea (U.S. Pat. No. 6,503,951, 2000).
The derivatives of Creatine and malonic, maleinic, fumaric, orotic acids and taurine (CN 10/249,338, 2003; U.S. Pat. No. 6,861,554, 2005; U.S. Pat. No. 6,166,249, 2000; CN 10/740,263, 2003) are indicated for medical nutrition as food additives; Creatine citrate (US 2004/077719, 2004) is recommended as a nootropic agent, as well as for using in cosmetic compositions. Among other Creatine derivatives, a magnesium salt of Creatine phosphate (CN 1709896, 2005) should be noted, which salt is indicated for the cardiac muscle.
The most similar to the claimed substances are Creatine esters, such as ethyl and benzyl esters (WO 02/22135, 2002), and compositions on their basis, which have a higher solubility in water and better permeability through the cell membrane in comparison with Creatine. Efficiency of the Creatine esters wasn't examined. However, it was assumed that the aforesaid derivatives being transferred into blood, and being acted upon by enzymes (esterases), are converted into Creatine. Preparations based on the Creatine esters are used as a food additive per os in the form of solutions, emulsions, pills, and capsules.
A disadvantage of the aforesaid compounds is their insufficient stability in the organism and low bioequivalence. It makes the use of Creatine esters in the solid forms or powders and in increased doses per day preferable.
At the present time, there is known a numerous group of drugs, capable of affecting the energy metabolism of the brain tissue, specifically, of activating the integrative functions of brain, and of the brain stability with regard to damaging factors. (M. D. Mashkovsky. Medications. M., Medicine; Goodman E. Gilman's. The Pharmacological Basis of Therapeutics, 11 ed, McGraw-Hill, Medical Publishing Division, New York 2006; RU 1 746 886, 1991, WO96/08527, 1996). In particular, the drug group includes: pyrrolidone derivatives (f.e., pyracetam) activating the energy exchange; drugs enhancing the cholinergic processes (f.e., amyridine, tacrine, glyatiline etc.; GABA-energy drugs (f.e., γ-aminobutyric acid, hopantenic acid, pycamylon, phenybut), activating enzymes of the Krebs cycle; antioxidants and membrane-protectors (f.e., mexidol, meclophenoxate, piritino, ubiquinone); drugs of a complex metabolic action (f.e., vinpocetine) optimizing the oxidation-reduction processes, enhancing of the energy metabolism.
The disadvantages the most of aforesaid substances are: a narrow spectrum of action associated with a considerable number of contra-indications, and moderate neuroprotective efficiency. At the same time, it's known that the clinical using of effective neuroprotectors would allow increasing the share of “small” strokes among ischemic damages in the cerebral blood flow, reducing the infarction zone sizes considerably, extending the period of “therapeutic window and protecting from the reperfusion injuries (Lancet, 2004, 363, 349-45).
Among of this drugs group, Actovegine is of the widest use, which drug is the nearest prior art substance to the claimed compounds with regard to its action. Actovegin contains deproteinized hemoderivative extracted from calf blood, used in the form of pills or solution for injections (Guide VIDAL, 2001, AstraPharmService, p. B-18).